Endocrine Control of Metabolism Flashcards
Metabolism
What is metabolism
what is intermediary metabolism
Metabolism is the study of the synthesis (anabolism) and degradation (catabolism) of the cellular constituents of living organisms.
Intermediary metabolism is the study of the central metabolic pathways in the cell, integrating sugar, fatty acid and amino acid metabolism.
Overview of energy metabolism
What do we eat and what is the end product of these after digestion>
How can all of these be fed into the krebs cycle? Via what? What happens after krebs cycle?
How can excess glucose be stored?
From our diet we intake fats, polysaccharides and proteins, the end product of digestion of these are fatty acids, glucose (or other monosaccharides) and amino acids.
All of these can be fed into the Krebs cycle via Acetyl CoA. The Krebs cycle drives the ETC which produces ATP. The Krebs cycle is the central integrating focus between carbohydrates, fats and amino acid and this is via the ACoA.
Glucose taken up by cells can enter glycolysis (glucose -> Acetyl CoA).
In the absence of O2 glycolysis can give energy but in oxygen presence pyruvate will be oxidised to ACoA and enter the Krebs cycle.
Same with fatty acids -> breakdown into Acetyl CoA by beta oxidation
Proteolysis breakdown of AA -> Acetyl CoA (or other TCA intermediates or ketones)
However, everything isn’t shuttled forward, all glucose isn’t put into Krebs, much of it is stored.
The fatty acids, glucose and AA can be taken from blood after eating and absorption from the gut. But between meals if there is nothing to absorb from the gut these nutrients can be released from stores in the body.
• Glucose -> Glycogen
• Fatty acids -> TAGs
Two Phases of Metabolism: Absorptive and Fasting
What is the absorptive state? When does it occur?
What is the state after this? what else can it be called?
What regulates the switching of states? Name a few hormones
Which one dominates in the absorptive state and which one dominates in the other state?
What are diabetogenic hromones?
The fed state or absorptive phase is the state of metabolism after a meal, for several hours, while absorption is going on. During this phase, nutrients are being absorbed from the gut and entering the circulation.
Several hours after a meal we enter the fasting state, by this we mean the condition of having an empty stomach (e.g. waking up in morning). It is also called the post-absorptive state.
Metabolic pathways switch between those in the fed state – when absorption and laying down of energy reserves is going on and the fasting state – when there are no nutrients to absorb from the gut and we live of stored nutrients.
This switching between metabolic state is regulated by hormones and a main point of this hormonal regulation is to maintain blood sugar levels. These hormones include:
Insulin: Dominates absorptive state, released as blood glucose rises and promotes storage (as glycogen) to decrease blood sugar.
Glucagon: Dominates post-absorptive state, function is nutrient release, such as raising blood glucose when levels drop
Cortisol, growth hormone
(somatotrophin), adrenaline: Release nutrients, raise blood sugar levels (called diabetogenic hormones because of this)
Effects of Insulin
What does insulin do and what 3 main tissues does it work with?
What other molecules does insulin have an effect on?
What does it stimulate and what does it inhibit? and what does it further inhibit?
Insulin stops blood glucose rising after a meal and does this by promoting uptake of glucose into three main tissues • Adipose tissue (fat) • Skeletal muscle • Cardiac muscle • Liver
Insulin also promotes uptake of free fatty acids and amino acids into adipose and muscle tissue.
It stimulates glycogen synthesis (esp. in muscle and liver) and inhibits glycogenolysis
Insulin also further inhibits gluconeogenesis, lipolysis and proteolysis
Absorptive State
How does glucose enter cells?
What happens immediately once it is in a cell?
What happens in small amounts?
What happens mostly to glucose and is stimulated by insulin?
What if there is excess glucose?
Blood glucose is rising due to a meal, it enters cells via GLUT protein channels (their expression stimulated by insulin).
Glucose enters a cell and is immediately phosphorylated to maintain diffusion gradient, so glucose keeps entering cell
With G6P we can put it into glycolysis and get pyruvate -> ACoA -> TCA, however this will only be a small amount in the absorptive state.
Instead most G6P will be taking the pathway of glycogenesis, converted into glycogen. This is stimulated be insulin.
If there was even more glucose than needed to be converted to glycogen, then the cell may decide that ACoA from G6P can be converted into fatty acids by lipogenesis.
The fatty acids can then be stored as fat (as TAGs).
Post-absorptive State
What happens when blood glucose is low? What is inhibited and what is released? What happens in the liver? What happens to glycogen? What happens to fat stores and what is this process called?
Why is the maintenance of blood glucose important? How does this affect the brain? what happens if too low glocose level?
Blood glucose low in fasting state, insulin release reduced/cut off. So the processes induced by insulin will stop.
The antagonistic hormone glucagon may be released which causes nutrient releasing pathways to stop blood glucose falling too low.
Glycogen will be converted back to G6P via glycogenolysis and in the liver G6P can be dephosphorylated into glucose which will diffuse out into the circulation where glucose is low (stimulated by glucagon).
In fasting state, we may get mobilisation of fat, the glycerol component of TAGs can be converted back into glucose as well as certain amino acids can be converted to glucose via pyruvate.
This is gluconeogenesis = the synthesis of glucose from non-carbohydrate starting point.
The reason why this maintenance of blood glucose is so important is down to the brain. This is because the brain is entirely dependent on aerobic metabolism and doesn’t have much of an ability to oxidise fatty acids.
- The brain therefore is reliant on glucose and it doesn’t have much of a capacity to store glycogen either so is reliant on constant, uninterrupted supply of glucose via the circulation.
- So, these functions of the fasting state can be thought of as being for the brain. Otherwise if it drops too low = coma -> death
Where and how do Insulin and Glucagon act?
Where does insulin act? (organs and what does it do there?)
Where does glucagon act and what does it do there?
In general insulin acts on the liver, muscle and adipose tissue, promoting storage:
Liver:
• Glycogenesis,
• Glycolysis,
• Lipogenesis
Muscle:
• Glucose uptake,
• Amino acid uptake,
• Glycogenesis
Adipose tissue:
• Glucose uptake,
• Free fatty acid uptake,
• Lipogenesis
Glucagon actions is generally thought to be just on the liver:
- Glycogenolysis
- Gluconeogenesis
- Ketogenesis
Even though glucagon doesn’t act on muscle or adipose tissue, the absence of insulin will favour the catabolic processes e.g. lipid breakdown
Major Metabolic Pathways in Skeletal Muscle
3 different pathways in muscles
what does insulin do to muscles? 3 things
what glucose receptor is situated on muscles? what is the fate of the glucose? what happens if very active muscle?
what is LPL and what how does this help muscles?
In muscle there are various pathways, ATP generation, glycogen synthesis (in absorptive state) and breakdown of glycogen energy (during fasting state).
Insulin does a number of things to muscle
o It stimulates glucose uptake via GLUT 4 transporters (increase their expression on cell membrane, so increases glucose permeability)
o It stimulates amino acid uptake
o Stimulates glycogenesis
No. of GLUT 4 increases, glucose moves in and gets phosphorylated
Some of that will enter glycolysis. The amount depending on level of muscle activity, if very hard exercise we will respire anaerobically and produce lactate which will diffuse out to blood and go to liver -> can be fed into gluconeogenesis
Fatty acids can be fed into TCA cycle.
LPL = An enzyme required for fats to be taken into cells
Fatty Acid and Glucose Metabolism in White Adipose Tissue
What is stored in adipose tissue?
What is the function of adipose tissue?
How are fatty acids transported to tissues?
Effecr of insulin on adipose tissue?
Why do lipids need a special transport?
When are chylomicrons only present and what state? transported where?
How are they broken down?
What happens to them at the liver and how are they released in a fasting state?
What happens to glucose at adipocyte?
Adipose tissue is where fat is stored, the free fatty acids from digestion have their long-term storage as TAGs.
So, function of adipose tissue is synthesis of TAG from fatty acids and glucose (store them) and also release fatty acids from storage.
Fatty acids are transported to tissues in lipoproteins.
Insulin
- Stimulates glucose uptake via GLUT 4 transporters
- Stimulates fatty acid uptake by stimulating lipoprotein lipase
- Lipogenesis
Because lipid is water insoluble, they can’t dissolve in the blood plasma, so are transported as lipoproteins.
Chylomicrons carry the absorbed fat from the gut, so are only present in absorptive phase. They can transport to liver, adipose tissue for example.
The transported fats (as TAGs) can be broken down at endothelial membrane by lipoprotein lipase. The fatty acids will be taken up by adipocytes and the liver and can be converted to TAGs and stored (they can then be later released again as fatty acids).
Many of these chylomicrons will pass by the liver and the fatty acids will be released as VLDLs, if in fasting phase the TAGs will be being transported in the VLDL particles and the same thing will happen (release of FA at tissues)
The bubble is an adipocyte that is next to a capillary, a chylomicron/VLDL particle passes by a lipoprotein lipase will breakdown the TAGs into fatty acids which will diffuse into the adipocyte. This process is insulin stimulated. The fatty acids can then be converted to TAGs in the adipocyte.
Glucose will also be taken up by adipocytes, it will then undergo the pathway of lipogenesis. The glucose -> ACoA via glycolysis pathway, the ACoA can then be converted to fatty acids.
Major Metabolic Pathways In The Liver
glucose, amino acid and fatty acid (what processes happen to each of these)
Glucose Metabolism:
o Glycogen formation
o Glycogenolysis
o Gluconeogenesis
Amino Acid Metabolism
o Lipogenesis
o Ketogenesis
o Gluconeogenesis
Fatty Acid Metabolism
o Lipogenesis
o Ketogenesis
Glucose and Amino Acid Metabolism in the Liver
How do you burn long term fat stores?
What is the problem with fatty acid oxidation and gluconeogenesis occurring at the same time?
Why is there a build of ACoA?
How does the liver work around this?
what is the benefit of this process?
How does the body utilise the product of this new method? and how does it benefit the brain?
If you want to burn your long term fat stores, you would mobilise your fats from lipid reserves, TAGs would be transported in VLDLs -> lipoprotein lipase would break them down -> fatty acids would be fed into Krebs cycle via beta oxidation through conversion to ACoA
There is a problem however, in the liver fatty acid oxidation and gluconeogenesis are occurring simultaneously.
So they can be in competition due to oxaloacetate being required for both processes.
o Oxidation of Acetyl CoA (produced by beta oxidation) to enter Krebs cycle
o Oxaloacetate to phosphoenol pyruvate for gluconeogenesis
Hence, we could get a buildup of ACoA, as if oxaloacetate is being used for gluconeogenesis ACoA cannot enter Krebs until there is an oxaloacetate molecule to bind with.
The way we get around this is ketogenesis. ACoA instead of entering the Krebs cycle it is metabolised into ketone bodies.
o These are acetoacetate, 3-hydroxybutyrate and acetone.
o The benefit of this is it reduces the demand for amino acids for gluconeogenesis and hence reduces protein breakdown.
The ketone bodies can enter into the circulation and be used by muscle where it is reconverted back to ACoA and enters Krebs to produce energy.
o This helps conserve the limited glucose for the brain (when low glucose), note that the brain can use ketone bodies in times of starvation, to a limited extent.
Keto acid formation in the liver: Ketoacidosis in type 1 diabetes
what does the body think is happening without insulin?
What does the lack of insulin cause?
How is there a buildup of ACoA?
How does ketoacidosis occur?
In diabetes, the formation of ketone bodies leads to a problem.
In type 1 diabetes mellitus there is absolute lack of insulin, the dominant hormone of the absorptive state. Without it, the body thinks it’s starving because insulin is released on eating to signify absorption.
The lack of insulin causes a free running of the processes usually inhibited by it. Gluconeogenesis the formation of glucose will occur, using oxaloacetate, there will also be beta oxidation of fatty acids -> conversion to ACoA.
Hence as the two are occurring there will be a build-up of ACoA and this will be shuttled to ketogenesis and there will be the formation of ketone bodies.
Ketone bodies are mildly acidic and so lower blood pH. Normally the bloods’ buffering capacity can control this, but in diabetes type 1 the buffering system is overwhelmed. So you get acidosis -> diabetic ketoacidosis.
Overview of the Metabolic Disturbances in Diabetes Mellitus
Why do you get a huge increase in glucose? (2 reasons)
What issues does this cause?
How does the kidney add to the acidosis problem?
You start of hyperglycemic, because glucose absorbed from the gut is not taken up by the tissues (as this is an insulin dependent process, so accumulates in blood)
At the same time, you also have body making glucose by gluconeogenesis due to the absence of insulin. Both causes a huge increase in blood sugar.
This cause osmotic problems:
o We will have glycosuria, glucose in the urea, because glucose will be filtrated from blood into the tubule, usually it would be reabsorbed but the glucose concentrations are higher than the capacity for reabsorption -> end up with glucose in urine.
o Causes osmotic diuresis, the high osmolarity in tubule will mean less water reabsorption -> causing dehydration = Symptoms: Polyurea, thirst
All this impairs the kidneys, so kidney not as good at functioning such as excreting H+ leading to acidosis.
- This adds to the problem of ketoacidosis -> Coma and Death
Defences against Hypoglycaemia
short term (3)
medium term
long term
In the short-term:
• Glucagon
• Epinephrine
• Sympathetic NS
In the medium-term:
• Ketogenesis provides a partial substitute for glucose, sparing muscle tissue from the destruction that would otherwise be needed to provide amino acid substrates for gluconeogenesis
In the long-term:
• Cortisol stimulates proteolysis to supply amino acid substrates for gluconeogenesis
Metabolic pathways serving energy storage
Glycogenesis
Synthesis of glycogen from glucose
Lipogenesis
Synthesis of FA from acetyl CoA
Triglyceride synthesis
Esterification of FA for storage as TG
